Method for producing optically active alpha-substituted proline
An optically active, proline technology, applied in the direction of organic chemistry, fermentation, etc., can solve the problems such as the inability to manufacture 2-methylpyrroline
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Embodiment 1
[0235] Production of 2-cyano-2-methylpyrrolidine and 2-methyl-1-pyrroline (in the above formula (2), R 1 =Me,R 2 =R 3 = H; step (a) uses sodium cyanide and ammonium acetate, reacted in methanol-water solvent)
[0236]
[0237] A flask was charged with 5-chloro-2-pentanone (2.41g, 20mmol), sodium cyanide (1.08g, 22mmol), ammonium acetate (4.62g, 60mmol), water (5ml) and methanol (2.5ml), And the mixture was reacted at 50°C for 3 hours. Ethyl acetate and 50 w / v% NaOH aqueous solution (3.2 ml) were added to the reaction mixture for partitioning, and the aqueous layer was re-extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated at 35°C, 80 hPa to obtain a brown oily substance (2.31 g). According to the NMR analysis results, this oily substance contains 2-cyano-2-methylpyrrolidine (60% by weight, 12.5mmol, yield 62%), 2-methyl-1-pyrroline (7% by weight, 2.0 mmol, yield 10%) and ethyl acetate (34% by weight) mixture. ...
Embodiment 2
[0240] The manufacture of α-methylprolinamide hydrochloride (in above-mentioned formula (3), R 1 =Me,R 2 =R 3 = H; step (b) is hydrated with hydrochloric acid)
[0241]
[0242] 2-cyano-2-methylpyrrolidine (0.40 g, 60% by weight, 2.2 mmol) obtained in Example 1 and concentrated hydrochloric acid (1 ml) were charged into a flask, and the mixture was reacted at room temperature for 15 hours. °C for 5 hours. After cooling to room temperature, 50 w / v% NaOH aqueous solution (1 ml) was added, and the mixture was extracted 6 times with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give crude 2-methylprolinamide. To the crude product were added methanol (0.1 ml), ethyl acetate (0.25 ml) and 4N hydrochloric acid-ethyl acetate solution (0.5 ml), and the mixture was ice-cooled. The crystals were collected by filtration to obtain α-methylprolinamide hydrochloride (92 mg, 0.56 mmol, yield 26%) as light brown crystals.
[0243] 1 H-NMR (400M...
Embodiment 3
[0245] Production of (S)-α-methylproline and (R)-α-methylprolinamide (in the above formulas (4) and (5), R 1 =Me,R 2 =R 3 = H; step (d) enzymatic resolution of the racemate)
[0246]
[0247] In a 2ml sample tube, the α-methylprolineamide hydrochloride obtained according to the method of Example 2 is made into a final concentration of 500g / L with 0.2M Tris damping fluid (pH 7.0), and the mixture is oxidized with 3% hydrogen The aqueous sodium solution was adjusted to pH 6.8. To this mixture (0.8 mL) was added an aqueous solution (0.2 mL) of peptidase R (trade name, manufactured by Amano Enzyme Inc., derived from Rhizopus oryzae) prepared at 50 g / L, and the mixture was stirred at 40° C. for several 800rpm reacted for 161 hours. As a result of purity analysis and optical purity analysis by HPLC analysis, the pure content of (S)-α-methylproline was 0.153mg (1.18mmol, yield 48.6%), and the optical purity was 99.3%ee, the The E value of the enzyme in the reaction was 1024. ...
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